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• W2897980045 abstract "We and other groups have shown that the eukaryotic initiation factor 2 alpha (eIF2α), a central regulator of protein synthesis, presents elevated activity in AD brains, as well as in diverse AD murine models. eIF2α promotes the uncoupling of the translation ternary complex, the machinery responsible for the majority of cellular translation, by inhibiting the activity of eIF2B. Therefore, modulating this pathway emerges as an attractive therapeutic approach. ISRIB is a small synthetic molecule that boosts the activity of eIF2B, enhancing the translational process dependent of the ternary complex. We sought to investigate whether ISRIB could counteract the cognitive impairment induced by amyloid β-olgimers (AβOs), neurotoxins that are closely related to AD pathology. We used a well-established model in our lab to study AβOs toxicity in vivo, consisting of a single injection of an AβOs suspension intracerebroventricularly (i.c.v.). Mice injected with AβOs present impaired memory in several different memory tasks even 10 days after the injection. To study ISRIB activity, we first performed i.c.v. injection of AβOs, and subsequently ISRIB was administered intraperitoneally on a daily basis, during one week. For APP/PS1 mice, we injected ISRIB for 2 weeks prior Morris Water Maze and Contextual Fear Conditioning tasks. Our results indicate that ISRIB prevents AβO-induced cognitive impairment in the Novel Object Recognition (NOR) task and in the Contextual Fear Conditioning (CFC) task, indicating that boosting the translation could counteract neurotoxic effects induced by AβOs. The hippocampus of mice injected with both AβOs and ISRIB presented lower levels of ATF4, when compared to the hippocampus of AβO-injected mice, which could indicate a possible pathway by which ISRIB could act through. The prevention of ATF4 levels by ISRIB was also seen in hippocampal neurons treated with AβOs. Finally, chronic injection of ISRIB in 10-month old APP/PS1 had neuroprotective effects in both Morris Water Maze and Contextual Fear Conditioning, without affecting locomotor activity of mice. Our data indicate that ISRIB could have a neuroprotective effect over AβOs activity, unraveling an alternative mechanism that could be exploited as a therapeutic target." @default.
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• W2897980045 date "2018-07-01" @default.
• W2897980045 modified "2023-10-16" @default.
• W2897980045 title "P3‐171: TARGETING TRANSLATION IMPAIRMENT TO RESTORE COGNITIVE DEFICITS IN ALZHEIMER'S DISEASE MODELS" @default.
• W2897980045 doi "https://doi.org/10.1016/j.jalz.2018.06.1529" @default.
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